Total clearance is the sum of clearances from individual organs, e.g.:

, where:

, where:

is urine concentration in mmol.L-1Function of glomerular filtration, reabsorption, and secretion.

is the urine flow in ml.min-1

is the plasma concentration in mmol.L-1

, where:

is the hepatic blood flow in ml.min-1

is the extraction ratio

Kinetics

Drug clearance can follow either first order or zero-order kinetics:

First-order KineticsA constant proportion of the drug in the body is eliminated per unit time.

Most drugs are eliminated by first order kinetics, as the capacity of the elimination system exceeds the concentration of drug

Zero-order kineticsA constant amount of drug is eliminated per unit time, independent of how much drug is in the body.

Occurs when there is saturation of enzyme systemsIt is also known as saturation kinetics for this reason.

e.g. Phenytoin follows first order kinetics at lower doses, but zero-order kinetics at doses within the therapeutic rangeThis is clinically relevant as the narrow therapeutic index means that toxic levels may occur rapidly with a small increase in dose.

e.g. Ethanol also follows zero-order kinetics within the "therapeutic range", as it is a very weak (doses are in grams) positive allosteric modulator of the GABAA receptor

Zero-order kinetics is concerning as:

Plasma concentrations will rapidly increase with only modest dose increase

There is essentially no steady state: if drug input exceeds output, plasma levels will continue to rise

Michaelis-Menten

The Michaelis-Menten equation describes the transition from first order to zero order kinetics as drug concentration increases:

Metabolism increases proportionally with concentration as long as the concentration of drug leaving the organ of metabolism (e.g. in the hepatic vein) is less than half of the maximal concentration of drug that organ can metabolise

This is ~1/3rd of the maximal rate of metabolism

Hepatic Metabolism

The principle organ of drug metabolism is the liver. Hepatic metabolism:

Important because genetic polymorphism leads to significant inter-patient variabilityMay result in significant over- or under-metabolism of drugs, and therefore significant inter-individual variability in response.

5-10% of the population are poor metabolisers

2-10% are intermediate metabolisers

1-2% are ultra-rapid metabolisers

Bulk of the population (70-90%) are extensive metabolisers

Clinical effect will depend on the type of drug

Pro-drugs

Extensive/ultra-rapid metabolisers will convert more drug to the active form, and see a greater effectMay lead to overdose.

Poor metabolisers will excrete more pro-drug prior to metabolism, and see a reduced clinical effect

Active drug

Extensive/ultra-rapid metabolisers will inactivate more drug, and see a reduced effect

Poor metabolisers will see a prolonged clinical effect

Clinical effect may be altered by enzyme interactions

e.g. Oxycodone use by an ultra-fast metaboliser, in combination with a CYP3A4 inhibitor (e.g. diltiazem) will result in a significant increase in the clinical effect of oxycodone

There is a high variability in plasma concentration between individuals due to the variation in liver blood flow

Drugs with high extraction ratios are generally independent of enzyme activity - decreasing enzyme activity from 99% to 95% has a minimal effect on hepatic clearance

The key exception is first pass metabolism, as the above change will result in a five-fold difference in dose reaching the systemic circulationTherefore drugs with a high extraction ratio have low PO bioavailability.

Low extraction ratioElimination is capacity-dependent.

Amount of free drug available for metabolism is greatly affected by the degree of protein binding

Metabolism is:

Largely independent of flowDrugs have good PO bioavailability.

Dependent on hepatocyte function and protein binding

Factors Affecting Hepatic Metabolism

Drug Factors

Patient Factors

Lipid solubility

Age

Ionisation

Obesity

Protein binding

Pregnancy

Enzyme competition

Genetics: Slow vs. fast acetylators

Hepatic flow/Extraction Ratio

Enzyme Inhibition/Induction

Hepatic disease

Smoking, ETOH

Organ Independent Metabolism

Mechanisms of organ indepedent metabolism include:

Hofmann DegradationSpontaneous degradation or metabolism of substances occurring in plasma.